Synthetic Studies toward Cyclopeptide Alkaloids

Abstract

식물체에서 추출된 cyclopeptide alkaloids는 다양하고 유용한 biological acitivity를 보인다. 이들은 특징적으로 β-hydroxy amino acid, styryl amine unit, ring bound amino acid를, 그리고 많은 경우에 질소를 포함한 5-membered ring을 가지고 있다. 본 연구의 목적은 (2,3)-disubstituted pyrrolidines를 효율적으로 비대칭 합성하는 것과, 천연물 amphibine D를 전합성하기 위한 합성 경로를 모색하는 것으로 크게 나눠 볼 수 있다. Part A에서는, 천연물의 전합성에 중요한 중간체로 쓰이는 2,3-cispyrrolidine 유도체는 그동안 여러 연구를 통하여 효율적인 합성 방법이 알려져 있으므로, 2,3-trans pyrrolidine 유도체의 합성을 중점적으로 연구하였다. 이 합성은 D-serine을 출발 물질로 하여 β-hydroxy ester의 Boc protection된 amino group과 hydrolysis 결과 형성된 carboxylic acid group 사이를 Bop-C1/DMAP/NEt_(3) system으로 intramolecular cyclization 하여 원하는 pyrrolidinone을 형성하였다. 이를 borane reduction 후 pyrrolidine 유도체가 8 단계 23%의 수득률로 얻어졌는데, 이때 2,3-trans와 cis form이 3:1의 비율로 형성되었다. Amphibine D의 합성 과정에서는 마찬가지로 D-serine을 출발물질로 하여 Meldrum's acid와의 coupling을 통해 2,3-cis 형태만 7 단계 34%의 수득률로 얻어졌다. Part B에 언급한 amphibine D의 전합성은 이전 연구를 바탕으로 하여 형성된 2,3-cis pyrrolidine 유도체를 중간체로 14-membered ring을 형성하였다. 이를 styryl amine unit까지 만들고 마지막으로 N,N-dimethyl-phenylalanylisoleucine과의 coupling만 남겨두게 되었는데, 이 과정에서 일반적으로 사용해왔던 Bop-C1나 DCC에 의한 activation으로는 반응이 진행되지 않아서 activation 방법에 대한 보다 자세한 연구를 선행키로 하였다. 이와 같은 연구를 통해 축적된 지식을 바탕으로 유사 천연물 mauritine D와 그의 epimer를 합성해서, epimerization과 관련된 biological activity 차이를 분석, 비교할 수 있을 것으로 기대된다.;Cyclopeptide alkaloids obtained from natural plants generally exhibit many useful biological activities. They are structurally interesting molecules with β-hydroxy amino acid, styryl amine unit, and ring bound amino acid moiety. Some cyclopeptide alkaloids contain pyrrolidine as β-hydroxy-α-amino acid unit. The present research is composed of two main projects. First, we studied the stereoselective synthesis of 2,3-trans pyrrolidine derivative. Second, we attempted the total synthesis of a 14-membered cyclopeptide alkaloid, amphibine D. Since the synthesis of 2,3-cis pyrrolidine derivative had already been accomplished during the course of the study in total synthesis of the naturally occuring cyclopeptide alkaloid, the successful synthesis of the 2,3-trans pyrolidine derivative could play a major role in total synthesis of both natural and unnatural 14-membered cyclopeptide alkaloids. Part A involves an efficient asymmetric synthesis of 2,3-trans pyrrolidine derivative from D-serine. The synthesis began with an unnatural amino acid, D-serine. After transformation of the amino group to carbamate and the hydroxyl group to tert-butyldimethylsilyl ether, the resulting free carboxylic acid was converted to the activated imidazolide. Unstable imidazolide was cautiously treated with lithiated ethyl acetate to afford the β-keto ester derivative in good yield. After stereoselective reduction of the ketone moiety to the corresponding secondary alcohols using potassium borohydride, the products were not separated but directly protected to the silyl ethers. Ester hydrolysis followed by intramolecular cyclization successfully produced N-containing 5-membered ring compounds. Borane reduction of the amide group produced the expected target molecule as well as its diastereomer. Two stereoisomers were separated and the target 2,3-trans pyrrolidine derivative was obtained in overall eight step reactions and 23% yield. The ratio of 2,3-trans pyrrolidine to 2,3-cis was found to be 3:2. Alternatively, the 2,3-cis derivative could also be obtained from D-serine using Meldrum's acid activation method in overall seven step reactions and 34% yield. Part B describes our on-going efforts for the total synthesis of amphibine D. After series of sequential reactions, we were able to synthesize the 14-membered macrolactam which was subjected to the elimination reaction to form the styryl amino unit. The final step to complete the total synthesis of the natural product was to couple the macrocycle with appropriate dipeptide side-chain. Unfortunately several attempts to finish the synthesis using Bop-Cl or DCC as peptide coupling reagent in various reaction conditions were unsuccessful, presumably due to the unstable characters of starting macrocycle or reaction intermediates. Study to find the pertinent procedure to couple the side chain with macrocycle for the completion of the 14-membered amphibine D is on-progress. In conclusion, we were able to find the proper conditions to synthesize 2,3-trans and 2,3-cis pyrrolidine diastereomers. They are now being utilized in some natural compound synthesis. The results of this study could provide with the futile background for completion of the total synthesis of amphibine D, mauritine D, and epi-mauritine D.